(1) Field of the Invention
The present invention generally relates to inhibition of corepressor binding to BCL6. More specifically, the invention is directed to compositions and methods for inhibiting corepressor binding to the BCL6 lateral groove.
(2) Description of the Related Art
References Cited
Adams, J., Kelso, R., and Cooley, L. (2000). The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol 10, 17-24.
Ahmad, K. F., Engel, C. K., and Privé, G. G. (1998). Crystal structure of the BTB domain from PLZF. Proc Natl Acad Sci USA 95, 12123-12128.
Albagli-Curiel, O. (2003). Ambivalent role of BCL6 in cell survival and transformation. Oncogene 22, 507-516.
Ball, H. J., Melnick, A., Shaknovich, R., Kohanski, R. A., and Licht, J. D. (1999). The promyelocytic leukemia zinc finger (PLZF) protein binds DNA in a high molecular weight complex associated with cdc2 kinase. Nucleic Acids Res 27, 4106-4113.
Ball, L. J., Jarchau, T., Oschkinat, H., and Walter, U. (2002). EVH1 domains: structure, function and interactions. FEBS Lett 513, 45-52.
Bardwell, V. J., and Treisman, R. (1994). The POZ domain: a conserved protein-protein interaction motif. Genes Dev 8, 1664-1677.
Baron, B. W., Anastasi, J., Thirman, M. J., Furukawa, Y., Fears, S., Kim, D. C., Simone, F., Birkenbach, M., Montag, A., Sadhu, A., et al. (2002). The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression: implications for a role of BCL6 in the down-regulation of apoptosis. Proc Natl Acad Sci USA 99, 2860-2865.
Brunger, A. T., Adams, P. D., Cloare, G. M., DeLano, W. L., Gros, P., Grosse-Kunstleve, R. W., Jiang, J. S., Kuszewski, J., Nilges, M., and Pannu, N. S. (1998). Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallographic D54, 905-921.
Calame, K. L., Lin, K. I., and Tunyaplin, C. (2003). Regulatory mechanisms that determine the development and function of plasma cells. Annu Rev Immunol 21, 205-230.
Costoya, J. A., and Pandolfi, P. P. (2001). The role of promyelocytic leukemia zinc finger and promyelocytic leukemia in leukemogenesis and development. Curr Opin Hematol 8, 212-217.
Cull, M. G., and Schatz, P. J. (2000). Biotinylation of proteins in vivo and in vitro using small peptide tags. Methods Enzymol 326, 430-440.
David, G., Alland, L., Hong, S. H., Wong, C. W., DePinho, R. A., and Dejean, A. (1998). Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 16, 2549-2556.
Deltour, S., Guerardel, C., and Leprince, D. (1999). Recruitment of SMRT/NCoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B. Proc Natl Acad Sci USA 96, 14831-14836.
Dent, A. L., Vasanwala, F. H., and Toney, L. M. (2002). Regulation of gene expression by the proto-oncogene BCL6. Crit. Rev Oncol Hematol 41, 1-9.
Dhordain, P., Albagli, O., Ansieau, S., Koken, M. H., Deweindt, C., Quief, S., Lantoine, D., Leutz, A., Kerckaert, J. P., and Leprince, D. (1995). The BTB/POZ domain targets the LAZ3/BCL6 oncoprotein to nuclear dots and mediates homomerisation in vivo. Oncogene 11, 2689-2697.
Dhordain, P., Albagli, O., Lin, R. J., Ansieau, S., Quief, S., Leutz, A., Kerckaert, J. P., Evans, R. M., and Leprince, D. (1997). Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proc Natl Acad Sci USA 94, 10762-10767.
Dhordain, P., Lin, R. J., Quief, S., Lantoine, D., Kerckaert, J. P., Evans, R. M., and Albagli, O. (1998). The LAZ3(BCL6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res 26, 4645-4651.
Fearon, D. T., Manders, P., and Wagner, S. D. (2001). Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science 293, 248-250.
Frankel, A. D. and Pabo, C. O. (1988). Cell 23, 1189-1193.
Grignani, F., De Matteis, S., Nervi, C., Tomassoni, L., Gelmetti, V., Cioce, M., Fanelli, M., Ruthardt, M., Ferrara, F. F., Zamir, I., et al. (1998). Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815-818.
Guidez, F., Ivins, S., Zhu, J., Soderstrom, M., Waxman, S., and Zelent, A. (1998). Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91, 2634-2642.
Hamilton, A. C., Inglese, J., and Ferrer, M. (2003). A PDZ domain-based assay for measuring HIV protease activity: Assay design considerations. Protein Sci 12, 458-467.
He, L. Z., Guidez, F., Tribioli, C., Peruzzi, D., Ruthardt, M., Zelent, A., and Pandolfi, P. P. (1998). Distinct interactions of PML-RARalpha and PLZFRARalpha with co-repressors determine differential responses to R A in APL. Nat Genet. 18, 126-135.
Hong, S. H., David, G., Wong, C. W., Dejean, A., and Privalsky, M. L. (1997). SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. Proc Natl Acad Sci USA 94, 9028-9033.
Huynh, K. D., and Bardwell, V. J. (1998). The BCL6 POZ domain and other POZ domains interact with the co-repressors N—CoR and SMRT. Oncogene 17, 2473-2484.
Huynh, K. D., Fischle, W., Verdin, E., and Bardwell, V. J. (2000). BCoR, a novel corepressor involved in BCL6 repression. Genes Dev 14, 1810-1823.
Kaplan, J., and Calame, K. (1997). The ZiN/POZ domain of ZF5 is required for both transcriptional activation and repression. Nucleic Acids Res 25, 1108-1116.
Kay, B. K., Williamson, M. P., and Sudol, M. (2000). The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J 14, 231-241.
Kobayashi, A., Yamagiwa, H., Hoshino, H., Muto, A., Sato, K., Morita, M., Hayashi, N., Yamamoto, M., and Igarashi, K. (2000). A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through the BTB/POZ domain. Mol Cell Biol 20, 1733-1746.
Kreusch, A., Pfaffinger, P. J., Stevens, C. F., and Choe, S. (1998). Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392, 945-948.
Kuppers, R., and Dalla-Favera, R. (2001). Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580-5594.
Ladbury, J. E., Lemmon, M. A., Zhou, M., Green, J., Botfield, M. C., and Schlessinger, J. (1995). Measurement of the binding of tyrosyl phosphopeptides to SH2 domains: a reappraisal. Proc Natl Acad Sci USA 92, 3199-3203.
Lemercier, C., Brocard, M. P., Puvion-Dutilleul, F., Kao, H. Y., Albagli, O., and Khochbin, S. (2002). Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor. J Biol Chem 277, 22045-22052.
Li, J. Y., English, M. A., Ball, H. J., Yeyati, P. L., Waxman, S., and Licht, J. D. (1997). Sequence-specific DNA binding and transcriptional regulation by the promyelocytic leukemia zinc finger protein. J Biol Chem 272, 22447-22455.
Li, X., Peng, H., Schultz, D. C., Lopez-Guisa, J. M., Rauscher, F. J., 3rd, and Marmorstein, R. (1999). Structure-function studies of the BTB/POZ transcriptional repression domain from the promyelocytic leukemia zinc finger oncoprotein. Cancer Res 59, 5275-5282.
Lin, R. J., Nagy, L., Inoue, S., Shao, W., Miller, W. H., Jr., and Evans, R. M. (1998). Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391, 811-814.
Lin, R. J., Sternsdorf, T., Tini, M., and Evans, R. M. (2001). Transcriptional regulation in acute promyelocytic leukemia. Oncogene 20, 7204-7215.
Mahmoudi, T., Katsani, K. R., and Verrijzer, C. P. (2002). GAGA can mediate enhancer function in trans by linking two separate DNA molecules. EMBO J. 21, 1775-1781.
Melnick, A., Ahmad, K. F., Arai, S., Polinger, A., Ball, H., Borden, K. L., Carlile, G. W., Privé, G. G., and Licht, J. D. (2000). In-depth mutational analysis of the promyelocytic leukemia zinc finger BTB/POZ domain reveals motifs and residues required for biological and transcriptional functions. Mol Cell Biol 20, 6550-6567.
Melnick, A., Carlile, G., Ahmad, K. F., Kiang, C. L., Corcoran, C., Bardwell, V., Privé, G. G., and Licht, J. D. (2002). Critical residues within the BTB domain of PLZF and BCL6 modulate interaction with corepressors. Mol Cell Biol 22, 1804-1818.
Melnick, A., and Licht, J. D. (1999). Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93, 3167-3215.
Ng D, Thakker N, Corcoran C M, Donnai D, Perveen R, Schneider A, Hadley D W, Tifft C, Zhang L, Wilkie A O, van der Smagt J J, Gorlin R J, Burgess S M, Bardwell V J, Black G C, Biesecker L G. (2004). Nat. Genet. 36, 411-416.
Niu, H. (2002). The proto-oncogene BCL6 in normal and malignant B cell development. Hematol Oncol 20, 155-166.
Niu, H., Cattoretti, G., and Dalla-Favera, R. (2003). BCL6 Controls the Expression of the B7-1/CD80 Costimulatory Receptor in Germinal Center B Cells. J Exp Med 198, 211-221.
Otwinowski, Z., and Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. Methods in Enzymology: Macromolecular Crystallography Part A 276, 307-326.
Pasqualucci, L., Migliazza, A., Basso, K., Houldsworth, J., Chaganti, R. S., and Dalla-Favera, R. (2003). Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101, 2914-2923.
Pawson, T., and Nash, P. (2003). Assembly of cell regulatory systems through protein interaction domains. Science 300, 445-452.
Prehoda, K. E., Lee, D. J., and Lim, W. A. (1999). Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly. Cell 97, 471-480.
Scheldrick, G. M., and Schneider, T. R. (1997). SHELXL: high-resolution refinement. Methods Enzymol 277, 319-343.
Shaffer, A. L., Lin, K. I., Kuo, T. C., Yu, X., Hurt, E. M., Rosenwald, A., Giltnane, J. M., Yang, L., Zhao, H., Calame, K., and Staudt, L. M. (2002). Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51-62.
Shaffer, A. L., Yu, X., He, Y., Boldrick, J., Chan, E. P., and Staudt, L. M. (2000). BCL6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199-212.
Shen, H. M., Peters, A., Baron, B., Zhu, X., and Storb, U. (1998). Mutation of BCL6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750-1752.
Staudt, L. M. (2002). Gene expression profiling of lymphoid malignancies. Annu Rev Med 53, 303-318.
Stebbins, C. E., Kaelin, W. G., Jr., and Pavletich, N. P. (1999). Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284, 455-461.
Sudol, M., Sliwa, K., and Russo, T. (2001). Functions of WW domains in the nucleus. FEBS Lett 490, 190-195.
Terwilliger, T. C., and Berendzen, J. (1999). Automated MAD and MIR structure solution. Acta Crystallogr D Biol Crystallogr 55 (Pt 4), 849-861.
Toney, L. M., Cattoretti, G., Graf, J. A., Merghoub, T., Pandolfi, P. P., Dalla-Favera, R., Ye, B. H., and Dent, A. L. (2000). BCL6 regulates chemokine gene transcription in macrophages. Nat Immunol 1, 214-220.
Wallace A C, Laskowski R A & Thornton J M (1995). LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Prot. Eng., 8, 127-134.
Wang, X., Li, Z., Naganuma, A., and Ye, B. H. (2002). Negative autoregulation of BCL6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci USA 99, 15018-15023.
Wong, C. W., and Privalsky, M. L. (1998). Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL6. J Biol Chem 273, 27695-27702.
Ye, B. H. (2000). BCL6 in the pathogenesis of non-Hodgkin's lymphoma. Cancer Invest 18, 356-365.
Zelent, A., Guidez, F., Melnick, A., Waxman, S., and Licht, J. D. (2001). Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20, 7186-7203.
Zhang, H., Okada, S., Hatano, M., Okabe, S., and Tokuhisa, T. (2001). A new functional domain of Bcl6 family that recruits histone deacetylases. Biochim Biophys Acta 1540, 188-200.
The BTB domain is a highly conserved, widely distributed protein-protein interaction motif found in a family of transcription factors that play critical roles in cellular differentiation, development and neoplasia. Several BTB/zinc finger proteins, including B-cell lymphoma 6 (BCL6) and promyelocytic leukemia zinc finger (PLZF), are transcriptional repressors that are implicated in human malignancy (Albagli-Curiel, 2003; Costoya and Pandolfi, 2001; Dent et al., 2002; Lin et al., 2001; Melnick and Licht, 1999). Both the BCL6 and PLZF proteins consist of an N-terminal BTB domain, followed by a central region of several hundred residues that are predicted to have little or no fixed 3D structure, and end with a series of C2H2-type zinc finger domains at the C-terminus. This general type of architecture is seen in 43 of the over 200 known human BTB domain proteins (GGP and P. J. Stogios, http://xtal.uhnres.utoronto.ca/prive/btb.html). A second major class of BTB domain proteins contain C-terminal kelch β-propeller repeats, and many of these are thought to be involved in cytoskeletal functions, although some of these are involved in transcription regulation (Adams et al., 2000). The core BTB domain fold is also found in the T1 domain of voltage-gated K+ channels (Kreusch et al., 1998), and in the ElonginC/Skp1 proteins (Stebbins et al., 1999).
Despite the architectural similarity of the BTB/zinc finger transcription factors, these can function as repressors, activators, or both and the BTB domain plays a central role in these activities (Kaplan and Calame, 1997; Kobayashi et al., 2000; Mahmoudi et al., 2002). The majority of BTB/zinc finger proteins, however, are thought to be transcriptional repressors, and several of these mediate their effects through the recruitment of histone deacetylase complexes. Thus, in BCL6, the BTB domain mediates interactions with the SMRT, N—CoR, BCoR and mSin3A corepressors, as well as with histone deacetylase 1 (HDAC-1), and repression is relieved with HDAC inhibitors (David et al., 1998; Dhordain et al., 1997; Dhordain et al., 1998; Grignani et al., 1998; Guidez et al., 1998; He et al., 1998; Hong et al., 1997; Huynh and Bardwell, 1998; Huynh et al., 2000; Lin et al., 1998; Wong and Privalsky, 1998). The recruitment of a histone deacetylase complex is not a universal property of the BTB domain, as evidenced by the fact that the BTB domains of HIC1 and gFBP-B do not interact with these factors (Deltour et al., 1999). Thus, it is clear that distinct mechanisms are used by different BTB domains in order to carry out a variety of biological effects.
In the B-cell lineage, the BCL6 protein is expressed in germinal center (GC) B-cells, but not in pre-B cells or in differentiated progenies such as plasma cells. Because BCL6 expression is tightly regulated during lymphoid differentiation, its down-regulation in post-GC B-cells may be necessary for further plasma/memory cell differentiation. Some of the more notable genes that are repressed by BCL6 include the B lymphocyte-induced maturation protein (blimp-1), a transcriptional repressor of c-myc which plays a key role in differentiation of B-cells to plasma cells (Shaffer et al., 2002), the cell cycle control genes p27kip1 and cyclin D2 (Shaffer et al., 2000), the programmed cell death-2 protein (PDCD2) (Baron et al., 2002), and B7-1/CD80 (Niu et al., 2003). Chromosomal translocations upstream of the BCL6 gene are observed in approximately 30-40% of diffuse large B-cell lymphomas (DLBCL) and in 5-14% of follicular lymphomas (FL) (Kuppers and Dalla-Favera, 2001; Niu, 2002; Ye, 2000). In addition, the promoter region of BCL6 is targeted by somatic hypermutation in GC B-cells (Pasqualucci et al., 2003; Shen et al., 1998; Wang et al., 2002). Thus, a B-cell with an activated BCL6 gene may be trapped at the GC stage due to the repression of differentiation and cell-cycle control proteins (Calame et al., 2003; Dent et al., 2002; Fearon et al., 2001; Staudt, 2002). In addition to its role in lymphoid cells, BCL6 represses the expression of the chemokines MCP-1, MCP3 and MRP-1 in macrophages and is an important negative regulator of TH-2 type inflammation (Toney et al., 2000).
Due to the importance of BCL6 in B-cell differentiation and leukemia development, there is a need for greater understanding of the mechanisms that control BCL6 interactions, particularly interactions with the corepressors SMRT, N—CoR and BCoR. The present invention addresses that need.